JP7167280B2 - Topical formulations of JAK inhibitors - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit of U.S. Provisional Patent Application No. 61/347,132, filed May 21, 2010, which is hereby incorporated by reference in its entirety. It is claimed.

The present invention provides (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutical Pharmaceutical formulations for topical skin application containing salts that are acceptable to the skin and use in the treatment of skin disorders.

Protein kinases (PKs) regulate many biological processes including cell proliferation, survival, differentiation, organogenesis, morphogenesis, angiogenesis, tissue repair and regeneration. Protein kinases also play specialized roles in many human diseases, including cancer. Cytokines, small polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation and can modulate both pro- and anti-inflammatory responses so that the host can respond appropriately to pathogens. A wide range of cytokine signaling involves the Janus kinase family of protein tyrosine kinases (JAKs) and signaling and activators of transcription (STATs). There are four known mammalian JAKs, these are JAK1 (Janus kinase-1), JAK2, JAK3 (Janus kinase, leukocyte; JAKL; also known as L-JAK) and TYK2 (protein-tyrosine kinase 2). .

Cytokine-stimulated immune and inflammatory responses contribute to the pathogenesis of disease, i.e., pathologies such as severe combined immunodeficiency (SCID) resulting from suppression of the immune system, while overactive or inappropriate Immune/inflammatory responses contribute to autoimmune disease pathologies (eg, asthma, systemic lupus erythematosus, thyroiditis, myocarditis), and diseases such as sclerosis and osteoarthritis (1).

Defects in JAK expression are associated with many disease states. For example, Jak-/- mice are stunted at birth, fail to lactate, and die perinatally (Non-Patent Document 2). Jak2−/− mouse embryos are anemic and die around 12.5 days post-mating due to the absence of terminal erythropoiesis.

The JAK/STAT pathway, and in particular all four JAKs, are thought to play a role in the pathogenesis of asthmatic reactions, chronic embolic respiratory disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. It is Multiple cytokines signaling through JAKs are associated with inflammatory diseases of the upper respiratory tract, such as diseases that develop in the nose and sinuses (e.g., rhinitis and sinusitis), whether classic allergic reactions or not. associated with symptoms. The JAK/STAT pathway has also been implicated in inflammatory diseases/conditions of the eye and chronic allergic reactions.

Activation of JAK/STAT in cancer is either by cytokine stimulation (eg IL-6 or GM-CSF) or endogenous to JAK signaling such as SOCS (suppressor of cytokine signal) or PIAS (protein inhibitor of activated STAT). may be caused by a decrease in sexual suppressors (Non-Patent Document 3). Activation of STAT signaling, as well as other pathways downstream of JAK, such as Akt, has been associated with poor prognosis in many cancer types (Non-Patent Document 4). Elevated levels of circulating cytokines signaling through JAK/STAT exert causative effects in cachexia and/or chronic fatigue. Thus, JAK inhibition may be beneficial to cancer patients because it works beyond potential anti-tumor activity.

Inhibition of JAK kinases is also predicted to have therapeutic benefit in skin immune diseases such as psoriasis and in patients who develop skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it is generally accepted that activated T lymphocytes are important in the maintenance of this disease and the associated psoriatic plaques (Non-Patent Document 5). Psoriatic plaques contain multiple epidermal layers with significant immune infiltration, including leukocytes and monocytes, and increased keratinocyte proliferation. Initial activation of immune cells in psoriasis occurs by unclear mechanisms, but its maintenance is thought to depend on several inflammatory cytokines, in addition to various chemokines and growth factors (Non-Patent Reference 6). Interleukins-2, -4, -6, -7, -12, -15, -18, and -23 and many of these, including GM-CSF and IFNg, signal through Janus (JAK) kinases (Non-Patent Document 7). Blocking signaling at the level of JAK kinases may therefore have therapeutic benefit in patients affected by psoriasis or other immune disorders of the skin.

Ortmann, R.; A. , T. Cheng et al. (2000) Arthritis Res 2(1): 16-32 Rodig, S.; J. , M. A. Meraz et al. (1998) Cell 93(3):373-83. Boudny, V.; , and Kovarik, J.; Written by Neoplasm. 49:349-355, 2002 Bowman, T.; et al., Oncogene 19:2474-2488, 2000. Gottlie, A.B. et al., Nat Rev Drug Disc. , 4:19-34 JCI, 113:1664-1675 Adv Pharmacol. 2000;47:113-74

Given the usefulness of JAK inhibitors in treating skin disorders, improved topical formulations of JAK inhibitors are needed. In particular, there is a need for stable, easily applied formulations of JAK inhibitors with good skin penetration properties. The formulations of the present invention, as well as the methods described herein, are directed to these needs and other objectives.

(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, a Potent JAK1/JAK2 Inhibitor , and pharmaceutically acceptable salts thereof, are disclosed in U.S. Pat. No. 7,598,257, U.S. Patent Publication No. 2009/0181959, and U.S. Pat. 0312259, previously described. The present invention is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) suitable for topical administration and treatment of skin disorders -Oil-in-water formulations of 3-cyclopentylpropanenitrile are described.

Accordingly, the present invention provides a pharmaceutical formulation, especially for topical skin application, which pharmaceutical formulation comprises
oil-in-water emulsion and (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or its pharmaceutical A therapeutically effective amount of a therapeutic agent that is an acceptable salt is included.

The present invention also provides a method of treating skin disorders comprising applying the pharmaceutical formulations described herein to an area of skin of a patient.

The present invention also provides a pharmaceutical formulation as described herein for use in treating skin disorders in a patient in need thereof.

The present invention also provides the use of the pharmaceutical formulations described herein for the preparation of a medicament for use in treating skin disorders in patients in need thereof.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will become apparent from the description and drawings, and from the claims.

Phosphate of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile of the present invention in water FIG. 2 shows a flow chart describing the manufacturing process for an oil formulation. 0.5%, 1.0% and 1.5% w/w (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- of the present invention Changes in lesion scores for subjects with chronic plaque psoriasis treated with an oil-in-water formulation of pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate (based on free base) over a period of 12 weeks. , compared to those treated with placebo (dotted line is baseline). 1.0% w/w (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane of the present invention Figure 3 shows photographs of a subject with chronic plaque psoriasis before (Fig. 3(a)) and 84 days after (Fig. 3(b)) treatment with an oil-in-water formulation of nitrile phosphate (free base basis). 1.0% w/w (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane of the present invention Figure 4 shows photographs of a subject with chronic plaque psoriasis before (Fig. 4(a)) and 84 days after (Fig. 4(b)) treatment with an oil-in-water formulation of nitrile phosphate (free base basis). . 1.5% w/w (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane of the present invention Figure 5 shows photographs of a subject with chronic plaque psoriasis before (Fig. 5(a)) and 84 days after (Fig. 5(b)) treatment with an oil-in-water formulation of nitrile phosphate (free base basis). . 0.5% w/w (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane of the present invention Figure 6 shows photographs of a subject with chronic plaque psoriasis before (Fig. 6(a)) and 84 days after (Fig. 6(b)) treatment with an oil-in-water formulation of nitrile phosphate (free base basis). . 1.0% w/w (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane of the present invention Figure 7 shows photographs of a subject with chronic plaque psoriasis before (Fig. 7(a)) and 84 days after (Fig. 7(b)) treatment with an oil-in-water formulation of nitrile phosphate (free base basis). .

Accordingly, the present invention provides a pharmaceutical formulation, especially for topical skin application, which pharmaceutical formulation comprises (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount.

In some embodiments, the pharmaceutical formulation comprises
Oil-in-water emulsion and (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a medicament thereof A therapeutically effective amount of a therapeutic agent that is a super-acceptable salt.

In some embodiments, an emulsion comprises water, an oil component and an emulsifier component.

As used herein, "emulsifier component" refers, in one aspect, to a substance or mixture of substances that maintains elements or particles in suspension within a liquid medium. In some embodiments, the emulsifier component causes the oil phase to form an emulsion when mixed with water. In some embodiments, emulsifier component refers to one or more nonionic surfactants.

Oil-in-water formulations have better appearance, spreadability and stability when compared to other formulations. The formulation has a viscous creamy appearance that provides good spreadability of the formulation on the skin. This good spreadability results in better skin penetration than similar anhydrous formulations. For example, oil-in-water formulations showed higher cumulative doses in a 24-hour human cadaver skin permeation study compared to anhydrous ointments. Without wishing to be bound by any particular theory, it is believed that this higher cumulative amount is due to the better spreadability of oil-in-water formulations compared to anhydrous ointments, which provides increased surface area for permeation. Conceivable. The higher viscosity for oil-in-water formulations also appears to be favorable for skin permeation, as high-viscosity cream formulations have better penetration of human cadaver skin compared to low-viscosity oil-in-water lotions.

The oil-in-water formulations described herein have good stability over a period of 3 months when stored in aluminum tubes at 25°C/60% relative humidity (RH) and 40°C/75% RH. and maintained an appropriate viscosity over time. In comparison, the water-in-oil formulation exhibited syneresis when stored at 40° C. (syneresis means the separation of the liquid from the emulsion).

The water-in-oil formulations of the present invention have also been tested in in vitro studies due to the dissolution of the API in base over time, resulting in highly variable skin permeation and lack of increase in permeation with increasing strength of the formulation. is less desirable than the formulation of

In a transfer study with freshly excised mouse skin, the oil-in-water formulation also showed increased permeability when the strength of the solubilizing cream was increased from 0.5% w/w to 1.5% w/w. However, such a trend was not observed in the water-in-oil formulation. Therefore, water-in-oil emulsions do not appear to have any advantage in terms of providing increasing permeability with increasing strength.

Additionally, the formulations described herein are relatively simple to manufacture due to the repeatable process of formulation. The resulting product is easily packaged. This formulation appears to have good stability and relatively constant permeability.

In some embodiments, the oil component is present in an amount from about 10% to about 40% by weight of the formulation.

In some embodiments, the oil component is present in an amount from about 17% to about 27% by weight of the formulation.

In some embodiments, the oil component is present in an amount from about 20% to about 27% by weight of the formulation.

In some embodiments, the oil component comprises one or more materials independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and silicone oils.

In some embodiments, the oil component comprises one or more materials independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone.

In some embodiments, the oil component comprises a sealant component.

In some embodiments, the sealant component is present in an amount from about 2% to about 15% by weight of the formulation.

In some embodiments, the sealant component is present in an amount from about 5% to about 10% by weight of the formulation.

As used herein, a "sealant component" is a hydrophobic sealant that forms an occlusive film on the skin that reduces transepidermal water loss (TEWL) by preventing evaporation of water from the stratum corneum. It refers to a mixture of drugs or hydrophobic drugs.

In some embodiments, sealant ingredients include fatty acids (e.g., lanolinic acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils & waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones. (e.g. dimethicone), sterols (e.g. cholesterol), vegetable or animal fats (e.g. coconut butter), vegetable waxes (e.g. carnauba wax), and wax esters (e.g. beeswax) including.

In some embodiments, the sealant component comprises one or more materials selected from lanolin fatty alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.

In some embodiments, the sealant component comprises petrolatum.

In some embodiments, the sealant component comprises white petrolatum.

In some embodiments, the oil component includes a hardener component.

In some embodiments, the hardener component is present in an amount from about 2% to about 8% by weight of the formulation.

In some embodiments, the hardener component is present in an amount of about 3% to about 6% by weight of the formulation.

In some embodiments, the hardener component is present in an amount from about 4% to about 7% by weight of the formulation.

As used herein, the term "hardener component" refers to a substance or mixture of substances that increases the viscosity and/or consistency of the formulation or improves the rheology of the formulation.

In some embodiments, the hardener component comprises one or more materials independently selected from fatty alcohols.

In some embodiments, the hardener component comprises one or more materials independently selected from C _12-20 fatty alcohols.

In some embodiments, the hardener component comprises one or more materials independently selected from C _16-18 fatty alcohols.

In some embodiments, the hardener component comprises one or more materials independently selected from cetyl alcohol and stearyl alcohol.

In some embodiments, the oil component includes an emollient component.

In some embodiments, the emollient component is present in an amount from about 5% to about 15% by weight of the formulation.

In some embodiments, the emollient component is present in an amount from about 7% to about 13% by weight of the formulation.

As used herein, the term "emollient" refers to an agent that softens or soothes the skin or soothes an irritated inner surface.

In some embodiments, the emollient comprises one or more substances independently selected from mineral oil and triglycerides.

In some embodiments, the emollient comprises one or more materials independently selected from light mineral oil and medium chain triglycerides.

In some embodiments, the emollient comprises one or more materials independently selected from light mineral oil, medium chain triglycerides, and dimethicone.

In some embodiments, water is present in an amount from about 35% to about 65% by weight of the formulation.

In some embodiments, water is present in an amount from about 40% to about 60% by weight of the formulation.

In some embodiments, water is present in an amount of about 45% to about 55% by weight of the formulation.

In some embodiments, the emulsifier component is present in an amount of about 1% to 9% by weight of the formulation.

In some embodiments, the emulsifier component is present in an amount of about 2% to 6% by weight of the formulation.

In some embodiments, the emulsifier component is present in an amount of about 3% to 5% by weight of the formulation.

In some embodiments, the emulsifier component is present in an amount of about 4% to 7% by weight of the formulation.

In some embodiments, the pharmaceutical formulation comprises an emulsifier component and a hardener component, wherein the total amount of emulsifier component and hardener component is at least about 8% by weight of the formulation.

In some embodiments, the emulsifier component comprises one or more materials independently selected from glyceryl fatty esters and sorbitan fatty esters.

In some embodiments, the emulsifier component comprises one or more materials independently selected from glyceryl stearate and polysorbate 20.

In some embodiments, the pharmaceutical formulation further comprises a stabilizer component.

In some embodiments, the stabilizer component is present in an amount from about 0.05% to about 5% by weight of the formulation.

In some embodiments, the stabilizer component is present in an amount from about 0.1% to about 2% by weight of the formulation.

In some embodiments, the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the formulation.

when used herein. A "stabilizer ingredient" refers to a substance or mixture of substances that improve the stability of a pharmaceutical formulation and/or the compatibility of the ingredients in the formulation. In some embodiments, the stabilizer component prevents aggregation of the emulsion and stabilizes the droplets in the oil-in-water emulsion.

In some embodiments, the stabilizer component comprises one or more substances independently selected from polysaccharides.

In some embodiments, the stabilizer component comprises xanthan gum.

In some embodiments, the pharmaceutical formulation further comprises a solvent component.

In some embodiments, the solvent component is present in an amount of about 10%-35% by weight of the formulation.

In some embodiments, the solvent component is present in an amount of about 15%-30% by weight of the formulation.

In some embodiments, the solvent component is present in an amount of about 20%-25% by weight of the formulation.

As used herein, the term "solvent component" refers to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-3-Cyclopentylpropanenitrile refers to a liquid substance or mixture of liquid substances in which 1-yl)-3-cyclopentylpropanenitrile or other substances can be dissolved. In some embodiments, the solvent component therein is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-Cyclopentylpropanenitrile, or a pharmaceutically acceptable salt thereof, is a liquid substance or mixture of liquid substances with suitable solubility. For example, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (free base) or its phosphorus Salt solubility is reported in Table 21. In some embodiments therein (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane Nitrile, or a pharmaceutically acceptable salt thereof (whichever is used), at least 10 mg/mL or more, at least 15 mg/mL or more when measured as described in Example 4 , or such substances or mixtures thereof that have a solubility of at least about 20 mg/mL or greater.

In some embodiments, the solvent component is one or more substances independently selected from alkylene glycols and polyalkylene glycols.

In some embodiments, the solvent component is one or more substances independently selected from propylene glycol and polyethylene glycol.

In some embodiments, the therapeutic agent is present in an amount of about 0.5% to about 1.5% by weight of the formulation on a free base basis.

In some embodiments, the therapeutic agent is present in an amount of about 0.5% by weight of the formulation, based on free base.

In some embodiments, the therapeutic agent is present in an amount of about 1% by weight of the formulation, based on free base.

In some embodiments, the therapeutic agent is present in an amount of about 1.5% by weight of the formulation on a free base basis.

In some embodiments, the therapeutic agent is (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl] Propanenitrile phosphate.

In some embodiments, the pharmaceutical formulation comprises
water from about 35% to about 65% by weight of the formulation;
an oil component from about 10% to about 40% by weight of the formulation;
an emulsifier component from about 1% to about 9% by weight of the formulation;
a solvent component from about 10% to about 35% by weight of the formulation;
Stabilizer component from about 0.05% to about 5% by weight of the formulation, and (R)-3-cyclopentyl from about 0.5% to about 1.5% by weight of the formulation, based on free base -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical formulation comprises
water from about 40% to about 60% by weight of the formulation;
an oil component, from about 15% to about 30% by weight of the formulation;
an emulsifier component from about 2% to about 6% by weight of the formulation;
a solvent component from about 15% to about 30% by weight of the formulation;
Stabilizer component from about 0.1% to about 2% by weight of the formulation, and (R)-3-cyclopentyl from about 0.5% to about 1.5% by weight of the formulation, based on free base -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical formulation comprises
water from about 45% to about 55% by weight of the formulation;
an oil component, from about 17% to about 27% by weight of the formulation;
an emulsifier component from about 3% to about 5% by weight of the formulation;
a solvent component from about 20% to about 25% by weight of the formulation;
Stabilizer component from about 0.3% to about 0.5% by weight of the formulation, and (R)-3 from about 0.5% to about 1.5% by weight of the formulation, based on free base -cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical formulation comprises
water from about 45% to about 55% by weight of the formulation;
an oil component, from about 17% to about 27% by weight of the formulation;
an emulsifier component from about 4% to about 7% by weight of the formulation;
a solvent component from about 20% to about 25% by weight of the formulation;
Stabilizer component from about 0.3% to about 0.5% by weight of the formulation, and (R)-3 from about 0.5% to about 1.5% by weight of the formulation, based on free base -cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments,
the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and dimethicone;
the emulsifier component comprises one or more substances independently selected from glyceryl fatty acids and sorbitan fatty esters;
the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols;
Stabilizers include one or more substances independently selected from polysaccharides.

In some embodiments,
the oil component comprises one or more materials independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone;
the emulsifier component comprises one or more materials independently selected from glyceryl stearate and polysorbate 20;
the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol;
Stabilizers include xanthan gum.

In some embodiments, the pharmaceutical formulation comprises
water from about 35% to about 65% by weight of the formulation;
a sealant component from about 2% to about 15% by weight of the formulation;
a curing agent component from about 2% to 8% by weight of the formulation;
an emollient component from about 5% to about 15% by weight of the formulation;
an emulsifier component from about 1% to about 9% by weight of the formulation;
from about 0.05% to about 5% by weight of the formulation of a stabilizer component;
from about 10% to about 35% by weight of the formulation of the solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical formulation comprises
water from about 40% to about 60% by weight of the formulation;
a sealant component from about 5% to about 10% by weight of the formulation;
a curing agent component from about 2% to 8% by weight of the formulation;
an emollient component, from about 7% to about 12% by weight of the formulation;
an emulsifier component from about 2% to about 6% by weight of the formulation;
from about 0.1% to about 2% by weight of the formulation of a stabilizer component;
from about 15% to about 30% by weight of the formulation of the solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical formulation comprises
water from about 45% to about 55% by weight of the formulation;
a sealant component from about 5% to about 10% by weight of the formulation;
a curing agent component of about 3% to 6% by weight of the formulation;
an emollient component, from about 7% to about 13% by weight of the formulation;
an emulsifier component from about 3% to about 5% by weight of the formulation;
from about 0.3% to about 0.5% by weight of the formulation of a stabilizer component;
from about 20% to about 25% by weight of the formulation of the solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical formulation comprises
water from about 45% to about 55% by weight of the formulation;
a sealant component from about 5% to about 10% by weight of the formulation;
a curing agent component from about 4% to 7% by weight of the formulation;
an emollient component, from about 7% to about 13% by weight of the formulation;
an emulsifier component from about 4% to about 7% by weight of the formulation;
from about 0.3% to about 0.5% by weight of the formulation of a stabilizer component;
from about 20% to about 25% by weight of the formulation of the solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical formulation comprises
water from about 45% to about 55% by weight of the formulation;
a sealant component of about 7% by weight of the formulation;
a curing agent component from about 4.5% to 5% by weight of the formulation;
an emollient component at about 10% by weight of the formulation;
an emulsifier component from about 4% to about 4.5% by weight of the formulation;
a stabilizer component at about 0.4% by weight of the formulation;
about 22% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the total amount of hardener component and emollient component is at least 8% by weight of the formulation.

In some embodiments,
The sealant component includes petrolatum,
The hardener component comprises one or more substances independently selected from one or more fatty alcohols, the emollient component comprises one or more substances independently selected from mineral oils and triglycerides,
the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;
The stabilizer component comprises one or more substances independently selected from polysaccharides,
The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

In some embodiments,
The sealant component includes white petrolatum,
the curing agent component comprises one or more substances independently selected from one or more of cetyl alcohol and stearyl alcohol;
The emollient component comprises one or more materials independently selected from light mineral oil, medium chain triglycerides, and dimethicone;
the emulsifier component comprises one or more materials independently selected from glyceryl stearate and polysorbate 20;
The stabilizer component comprises xanthan gum,
Solvent components include one or more substances independently selected from propylene glycol and polyethylene glycol.

In some embodiments, the pharmaceutical formulation further comprises an antimicrobial preservative component.

In some embodiments, the antimicrobial preservative component is present in an amount from about 0.05% to about 3% by weight of the formulation.

In some embodiments, the antimicrobial preservative component is present in an amount from about 0.1% to about 1% by weight of the formulation.

As used herein, the expression "antimicrobial preservative ingredient" is a substance or mixture of substances that inhibits microbial growth in a formulation.

In some embodiments, the antimicrobial preservative component comprises one or more materials independently selected from alkylparabens and phenoxyethanol.

In some embodiments, the antimicrobial preservative component is one or more materials independently selected from methylparaben, propylparaben, and phenoxyethanol.

In some embodiments, the pharmaceutical formulation further comprises a chelating agent component.

As used herein, the expression "chelator component" refers to a compound or mixture of compounds that has the ability to tightly bind metal ions.

In some embodiments, the chelating agent component comprises edetate disodium.

(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is each referred to in its entirety as It can be prepared as described in US Pat. No. 7,598,257 and US Patent Publication No. 2009/0181959, which are incorporated herein. The 1:1 phosphate of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is It may be prepared as described in US Patent Publication No. 2008/0312259, which is incorporated herein by reference in its entirety.

Compounds of the invention also include pharmaceutically acceptable salts of the compounds disclosed herein. As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound described herein. As used herein, the phrase "pharmaceutically acceptable" refers to substances that are acceptable for use in pharmaceutical applications from a toxicological point of view and that do not interact inappropriately with active ingredients. Point. Pharmaceutically acceptable salts include, but are not limited to, acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, of propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyrivic, methanesulfonic, ethanesulfonic, trienesulfonic, salicylic, benzoic, and similarly known acceptable acids Simple and di-salts, including those derived from organic and inorganic acids such as, but not limited to. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Ed., each of which is incorporated herein by reference in its entirety. , Mack Publishing Company, Easton, Pa.; , 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

It will also be appreciated that the compounds described herein may exist in solvated, eg hydrated, as well as unsolvated forms. deaf. It will be further understood that the invention comprehends all such solvated forms of the compounds.

As used herein, "wt % of formulation" means the percent concentration of an ingredient in a formulation on a weight/weight basis. For example, 1% w/w component A = [(mass of component A)/(total mass of formulation)] x 100.

As used herein, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, "% by weight of the formulation based on the free base" of or a pharmaceutically acceptable salt thereof means that the % w/w of the total weight of the formulation is (R)-3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is meant to be calculated based on the weight. For example, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 at "0.5% w/w based on free base" -yl)-3-cyclopentylpropanenitrile phosphate is 0.66 g of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate is present in the formulation (which is the free base, i.e. (R)-3-(4-( equivalent to 0.5 grams of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile).

In some embodiments, components are present exactly within the specified range (eg, the term "about" is absent). In some embodiments, "about" means plus or minus 10% of the number.

As will be appreciated, some components of the pharmaceutical formulations described herein can have multiple functions. For example, a given substance can act as both an emulsifier component and a stabilizer. In some such cases, the function of a given component may be considered singular even though its properties provide multiple functions. In some embodiments, each component of the formulation comprises a different substance or mixture of substances.

As used herein, the term "component" can mean a substance or mixture of substances.

As used herein, the term "fatty acid" refers to saturated or unsaturated fatty acids. In some embodiments the fatty acid is in a mixture of different fatty acids. In some embodiments, fatty acids have an average of about 8 to about 30 carbons. In some embodiments, fatty acids have an average of about 12-20, 14-20, or 16-18 carbons. Suitable fatty acids include, but are not limited to cetyl acid, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linoleic acid. acid, hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobehenic acid, and arachidonic acid, or mixtures thereof mentioned.

As used herein, the term "fatty alcohol" refers to saturated or unsaturated fatty alcohols. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbons. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidone alcohol, behenyl alcohol, isobehenyl alcohol. , selachyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.

As used herein, the term "polyalkylene glycol," used alone or in combination with other terms, refers to polymers containing oxyalkylene monomer units or copolymers of different oxyalkylene monomer units, wherein , the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "oxyalkylene," used alone or in combination with other terms, refers to a group of formula -O-alkylene-. In some embodiments, the polyalkylene glycol is polyethylene glycol.

As used herein, the term "sorbitan fatty ester" includes products derived from sorbitan or sorbitol and fatty acids and, optionally, poly(ethylene glycol) units, sorbitan esters and polyethoxyls. sorbitan esters. In some embodiments, the sorbitan fatty ester is a polyethoxylated sorbitan ester.

As used herein, the term "sorbitan ester" refers to a compound, or mixture of compounds, derived from the esterification of sorbitol with at least one fatty acid. Fatty acids useful for deriving sorbitan esters include, but are not limited to, those fatty acids described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), which include Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 ( sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). Other suitable sorbitan esters include those described by R.J. C. Rowe and P.S. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed.

As used herein, the term "polyethoxylated sorbitan ester" refers to a compound, or mixture of compounds, derived from the ethoxylation of a sorbitan ester. The polyoxyethylene portion of this compound may be between the fatty ester and sorbitan portions. As used herein, the term "sorbitan ester" refers to a compound or mixture of compounds derived from the esterification of sorbitol and at least one fatty acid. Fatty acids useful for deriving polyethoxylated sorbitan esters include, but are not limited to, those described herein. In some embodiments, the polyoxyethylene portion of the compound or mixtures thereof has from about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2-100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4-80 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4-40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4-20 oxyethylene units. Suitable polyethoxylated sorbitan esters include, but are not limited to, the Tween™ series (available from Uniqema), which includes Tween 20 (POE (20) sorbitan monolaurate), 21 ( POE (4) sorbitan monolaurate), 40 (POE (20) sorbitan monopalmitate), 60 (POE (20) sorbitan monostearate), 60K (POE (20) sorbitan monostearate), 61 (POE ( 4) sorbitan monostearate), 65 (POE (20) sorbitan tristearate), 80 (POE (20) sorbitan monooleate), 80K (POE (20) sorbitan monooleate), 81 (POE (5) sorbitan monooleate), and 85 (POE(20) sorbitan trioleate). As used herein, the abbreviation "POE" refers to polyoxyethylene. The number following the POE abbreviation refers to the number of oxyethylene repeat units in the compound. Other suitable polyethoxylated sorbitan esters include those described by R.H. C. Rowe and P.S. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th edition, polyoxyethylene sorbitan fatty acid esters. In some embodiments, the polyethoxylated sorbitan ester is polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.

As used herein, the term "glyceryl fatty ester" refers to mono-, di-, or triglycerides of fatty acids. Glyceryl fatty esters may be optionally substituted with a sulfonic acid group, or a pharmaceutically acceptable salt thereof. Suitable fatty acids for deriving glycerides of fatty acids include, but are not limited to, those described herein. In some embodiments, glyceryl fatty esters are mono-glycerides of fatty acids having 12-18 carbon atoms. In some embodiments, the glyceryl fatty ester is glyceryl stearate.

As used herein, the term "triglyceride" refers to triglycerides of fatty acids. In some embodiments, the triglyceride is a medium chain triglyceride.

As used herein, the term "alkylene glycol" refers to a group of formula -O-alkylene-, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 It has carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).

As used herein, the term "polyethylene glycol" refers to polymers containing ethylene glycol monomer units of the formula -O-CH2-CH2-. Suitable polyethylene glycols can have a free hydroxyl group at each end of the polymer molecule or can have one or more hydroxyl groups etherified with lower alkyl groups such as methyl groups. Also suitable are derivatives of polyethylene glycol with esterifiable carboxy groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight and can contain branching. In some embodiments, polyethylene glycol has an average molecular weight of about 200 to about 9,000. In some embodiments, polyethylene glycol has an average molecular weight of about 200 to about 5,000. In some embodiments, polyethylene glycol has an average molecular weight of about 200 to about 900. In some embodiments, polyethylene glycol has an average molecular weight of about 400. Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number following the dash in the name refers to the average molecular weight of the polymer.

It is further understood that although certain features of the present invention are described in separate embodiment descriptions for clarity, they may be applied in combination within a single embodiment description. Conversely, although various features of the invention are, for brevity, described in the description of a single embodiment, they can be applied separately or in any suitable subcombination.
Method

The pharmaceutical formulations of the invention are useful in treating skin disorders. In some embodiments, the skin disorder is an autoimmune bullous skin disease, such as pemphigus vulgaris (PV) or bullous pemphigoid (BP). In some embodiments, the skin disorder is psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). is. For example, certain substances, including some drugs, may cause skin sensitization when applied topically. In some embodiments, co-administration or sequential administration of topical formulations of the present invention together with agents that produce undesired sensitization is useful in treating such undesired sensitization or dermatitis. could be.

The present invention further provides methods of treating dermatological side effects of other pharmaceutical agents by administering compounds of the present invention. For example, many pharmaceuticals can cause unwanted allergic reactions that can manifest as acneiform rashes or related dermatitis. Examples of drugs with such undesirable side effects include anti-cancer agents such as gefitinib, cetuximab, erlotinib. The formulations of the invention can be administered systemically or locally in combination (simultaneously or sequentially) with pharmaceutical agents that have undesirable dermatological side effects. In some embodiments, one of the other pharmaceutical agents that develops contact dermatitis, allergic contact dermatitis, or similar skin disorders when applied topically in the absence of the formulations of the present invention. The formulations of the invention can be administered together with more than one. Accordingly, the formulations of the present invention encompass topical formulations that further include additional pharmaceutical agents that may cause dermatitis, skin disorders, or related side effects.

As used herein, the terms "individual" or "patient" are used interchangeably and refer to mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, It refers to any animal, including horses, or primates, and most preferably humans.

As used herein, the phrase "therapeutically effective amount" refers to the biological response or It refers to the amount of active compound or drug that elicits a medical response.

As used herein, the term "treating" or "treatment" means (1) preventing a disease; or preventing a disease, condition or disorder in an individual who has not yet experienced or developed a symptom; (2) inhibiting a disease; inhibiting the disease, condition or disorder (i.e., preventing further progression of the condition and/or symptoms), and (3) alleviating the disease; of alleviating a disease, condition or disorder (i.e., reversing the condition and/or symptoms) in an individual experiencing or developing the condition or symptoms of the disease, condition or disorder, so as to reduce Point to one or more.

Combination therapy e.g. chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, and Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors such as those described in International Patent Publication No. WO2006/056399, or One or more additional pharmaceutical agents, such as other agents, may be used in combination with the formulations of the present invention for the treatment of JAK-related diseases, disorders or conditions. One or more of these additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

Examples of chemotherapeutic agents include proteosome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

Examples of steroids include corticosteroids such as dexamethasone or prednisone.

Examples of Bcr-Abl inhibitors include compounds of the genera and species disclosed in US Pat. , and pharmaceutically acceptable salts thereof.

Examples of suitable Flt-3 inhibitors include compounds such as those disclosed in International Patent Publication Nos. WO 03/037347, WO 03/099771, and WO 04/046120, and their pharmaceutically acceptable and salts that are used.

Examples of suitable RAF inhibitors include compounds such as those disclosed in International Patent Publication Nos. WO00/09495 and WO05/028444, and pharmaceutically acceptable salts thereof.

Examples of suitable FAK inhibitors include International Patent Publication Nos. WO04/080980, WO04/056786, WO03/024967, WO01/064655, WO00/053595, and Included are compounds such as those disclosed in WO 01/014402, and pharmaceutically acceptable salts thereof.

In some embodiments, the formulations of the invention may be used in combination with one or more kinase inhibitors, including imatinib, particularly to treat patients resistant to imatinib or other kinase inhibitors.

In some embodiments, a corticosteroid such as dexamethasone is administered to the patient in combination with a compound of the invention, wherein dexamethasone is administered intermittently rather than continuously.

Labeled Compounds and Assay Methods Another aspect of the invention is to localize and quantify JAKs in tissue samples, including humans, and to identify JAK ligands by inhibiting the binding of labeled compounds. Second, it relates to formulations containing labeled active compounds (radiolabels, fluorescent labels, etc.) that are believed to be useful in both in vitro and in vivo assays, as well as imaging techniques. Accordingly, the present invention includes JAK assays containing such labeled compounds.

The present invention further includes formulations of isotopically labeled compounds. An "isotopically labeled" or "radiolabeled" compound is an atom having an atomic mass or mass number different from that typically found in nature (i.e., naturally occurring) are compounds in which one or more atoms are replaced or substituted by Suitable radionuclides for incorporation into compounds of the invention include, but are not limited to, ² H (also denoted as D for deuterium), ³ H (T for tritium ), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br , ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. The radionuclide incorporated into the radiolabeled compound will depend on the particular application of the radiolabeled compound. For example, compounds incorporating ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I, or ³⁵ S will generally be most useful for JAK labeling and competition assays in vitro. For radiographic imaging applications, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br will generally be most useful.

A "radiolabeled compound" or "labeled compound" is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S and ⁸² Br.

Kits The invention also includes pharmaceutical kits useful in the treatment or prevention of JAK-associated diseases or conditions, such as cancer, which contain one or more containers containing the pharmaceutical formulations of the invention. As will be appreciated by those of skill in the art, such kits may optionally comprise one or more of a variety of conventional containers, e.g., containers having one or more pharmaceutically acceptable carriers, additional containers, and the like. of pharmacy kit components. Instructions, such as either a package insert or a label, indicating the amounts of ingredients to be administered, guidelines for administration, and/or guidelines for mixing the ingredients can also be included in the kit.

The invention is explained in greater detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the scope of the invention in any way. Those of ordinary skill in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially the same results. In some embodiments, the invention provides pharmaceutical formulations comprising components identified in exemplary formulations (eg, Example 3), which are present in amounts approximately shown in Tables 2-5. do.

Example 1: (3R)- and (3S)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

Step 1. (2E)- and (2Z)-3-cyclopentyl acrylonitrile To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) was added diethylcyanomethyl phosphate (39.9 mL, 0.246 mol) in THF (300 mL). ) was added dropwise at 0°C. The cold bath was removed and the reaction was warmed to room temperature and then recooled to 0° C. at which point a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. added. The water bath was removed and the reaction was warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water and the aqueous phase was extracted three times with ether followed by two extractions with ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give a mixture containing 24.4 g of olefin isomers, which was used without further purification ( 89%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 ( d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-1.26 ( m, 16H).

Step 2: (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl]propanenitrile 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d in ACN (300 mL) ] pyrimidine (15.0 g, 0.0476 mol) was added 3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers) followed by DBU (15 mL, 0.0476 mol). 10 mol) was added. The resulting mixture was stirred overnight at room temperature. ACN was evaporated. The mixture was diluted with ethyl acetate and the solution was washed with 1.0N HCl. The aqueous phase was back extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/hexane gradient) to give a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, yielding 19.4 g of The racemic adduct was obtained (93%). The enantiomers were separated by preparative HPLC (OD-H, 15% ethanol/hexanes) and used separately in the next step to generate their corresponding final products. Although the final product arising from each separated enantiomer (see step 3) was found to be an active JAK inhibitor, the final product arising from the second peak eluted from preparative HPLC was more active than its enantiomer. was more active.
¹ H NMR (300 MHz, CDCl ₃ ): δ 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 ( s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m , 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), −0.06 (s, 9H); (ES): 437 (M+1).
Step 3: (3R)- and (3S)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 in DCM (40 mL) -yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer isolated as above) was added with TFA (16 mL) and stirred for 6 hours. Solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary evaporator, repeating this two more times to remove as much TFA as possible. Following this, the residue was stirred overnight in ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL). The solvent was removed in vacuo, water was added and the product was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to give crude product, which was purified by flash column chromatography (eluting with a gradient of methanol/DCM). . The resulting mixture was further purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H ₂ O containing 0.15% NH ₄ OH) to give the product (2.68 g, 58% ).
¹ H NMR (400 MHz, D ₆ -dmso): δ 12.11 (brs, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7. 60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS (ES): 307 (M+1).

試験管に（Ｒ）－３－（４－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－１Ｈ－ピラゾール－１－イル）－３－シクロペンチルプロパンニトリル（１５３．５ｍｇ）とリン酸（５６．６ｍｇ）を添加し、続いてイソプロピルアルコール（ＩＰＡ）（５．７５ｍＬ）を添加した。得られた混合物を透明になるまで加熱し、室温まで冷却し、次いで更に２時間攪拌した。沈殿物を濾過によって回収し、ケーキを冷ＩＰＡの０．６ｍＬで洗浄した。このケークを真空下で一定重量になるまで乾燥して、最終塩生成物（１７１．７ｍｇ）を得た。 Example 2: Phosphate of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (153.5 mg) in a test tube Phosphoric acid (56.6 mg) was added followed by isopropyl alcohol (IPA) (5.75 mL). The resulting mixture was heated until clear, cooled to room temperature and then stirred for an additional 2 hours. The precipitate was collected by filtration and the cake was washed with 0.6 mL cold IPA. The cake was dried under vacuum to constant weight to give the final salt product (171.7 mg).

The phosphate was shown to be a 1:1 salt by ¹ H NMR and the crystallinity was confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) gave a sharp melting peak at about 198.66°C. The product showed little weight loss up to 200° C. by TGA.

Example 3: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate in water Preparation of Oil Cream Formulation An oil-in-water cream formulation was prepared by adding (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl Propanenitrile phosphate (Example 2) was prepared at 0.5%, 1.0% and 1.5% by weight of the formulation (free base equivalent). The composition for a 15g tube is provided in Table 2 below. The three strength formulations were identical except for adjustments to the amount of purified water based on the amount of active ingredient. All excipients used in the formulation are of official grade (ie USP/NF or BP) or approved for use in topical products.

Formulation formulations for a typical 400 kg batch of cream formulations for Example 2 at 0.5, 1.0 and 1.5% are also provided in Tables 3, 4 and 5 respectively.

*実施例２の１．３２％は、（Ｒ）－３－（４－（７Ｈ－ピロロ［２，３－ｄ］ピリミジ
ン－４－イル）－１Ｈ－ピラゾール－１－イル）－３－シクロペンチルプロパンニトリル
遊離塩基の１．０％と等価である。

*1.32% of Example 2 is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl Equivalent to 1.0% of propanenitrile free base.

Oil-in-water cream formulations were synthesized according to the following procedure on either a 3.5 kg or 400 kg scale (when manufactured on a 3.5 kg batch size, amounts in Tables 3-5 were scaled down appropriately). ). Some batches underwent minor scale-up related changes, such as the size of the mixing vessel and mixer. Generally overhead mixers with high and low shear blades are suitable for this process. FIG. 1 is a flow chart representation of a process for producing an oil-in-water formulation. (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is referred to as "API ” is called.

Procedure 1. A paraben phase was prepared by mixing methylparaben and propylparaben with a portion of propylene glycol (see % in Tables 2-5).
2. The xanthan gum phase was then prepared by mixing xanthan gum with propylene glycol (see % in Tables 2-5).
3. An oil phase was then prepared by mixing light mineral oil, glyceryl stearate, polysorbate 20, white petrolatum, cetyl alcohol, stearyl alcohol, dimethicone and medium chain triglycerides. This phase is heated to 70-80° C. to melt and form a homogeneous mixture.
4. An aqueous phase was then prepared by mixing purified water, polyethylene glycol, and disodium EDTA. This phase is heated to 70-80°C.
5. The aqueous phase of step 4, the paraben phase of step 1, and Example 2 (Phosphate Salt of API) were combined to form a mixture.
6. The xanthan gum phase from step 2 was then added to the mixture from step 5.
7. The oil phase from step 3 was then combined with the mixture from step 6 under high shear mixing to form an emulsion.
8. Phenoxyethanol was then added to the emulsion from step 7. Mixing was continued and the product was then cooled under low shear.

A more uniform batch on a larger scale (eg 140 kg) can be achieved by gradually adding Example 2 to the water phase and then combining with the other phases. Similarly, a more uniform batch can be achieved with slower cooling (eg, by using room temperature water in the outer jacket of the reactor rather than cold water).

ANALYTICAL RESULTS AND STABILITY TESTS FOR CREAM FORMULATIONS A. Method The appearance of the creams was assessed visually. Viscosity was measured at 25° C. using a Brookfield viscometer. pH was measured in the final cream formulation. Microbial limit testing was performed according to USP. During the loading of the cream into the tube, the fill weight was analyzed as an in-process test.

Assay, related substances, identity and content uniformity were determined in the formulations by gradient reverse phase HPLC with UP detection at 294 nm. Waters HPLC was run to 40 using mobile phase A of 2 mL TFA (0.05% TFA) into 4 L water or mobile phase B of 2 mL TFA (0.05% TFA) into 4 L of methanol. C. with a Zorbax SB-C18 column (3.5 μm, 4.6×150 nm) at a flow rate of 1.0 mL/min.

B. Results Results are shown below (Table 6) for 3.5 kg batches of Example 2 (based on free base (API)) at 0.5%, 1% and 1.5% strength.

Stability data from batches of cream formulations at 0.5, 1.0 and 1.5% w/w strength stored in 15 g aluminum tubes are provided in Tables 7-10 and 19-20. . Additionally, stability data from batches of cream formulations at 0.5, 1.0 and 1.5% w/w strength, sealed in amber glass bottles (2 oz., with Teflon caps) are shown in Table 13- 17, while longer-term stability data for the 1.0% w/w formulation packaged in 16 oz. amber glass bottles are shown in Tables 11-12. Preliminary stability data for the pharmaceutical formulations did not show any chemical instability after 3 months storage at 25°C/60% RH and 40°C/75% RH in either encapsulated form. A change in viscosity was observed for formulations stored in amber glass bottles after 3 months of storage at 40° C./75% RH. However, physical evaluation of the pharmaceutical formulation did not show any phase separation. Acceptance criteria are shown below.

Example 4: Solubility Test (R)-3-(4-7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (free base) Or to determine the solubility of its phosphate, about 5 mL of a potential solvent was added to about 50 mg of API or its salt at room temperature. The mixture was suspended and spun on a wheel. When the mixture became a clear solution, more solid material was added. The suspension was allowed to suspend for 24 hours. Samples were filtered through a 0.2 micrometer filter. The liquid portion was collected and diluted with 50/50 aqueous methanol/water. Concentrations of diluted samples were analyzed by HPLC. If the free base or salt is fairly insoluble, the results are approximate only.

Example 5: Other Topical Formulations Three different topical formulations incorporating acid salts were also prepared. The compositions of 1% w/w dispersion cream (water-in-oil formulation), 1% w/w anhydrous ointment, and 1% w/w lotion are outlined in Table 22 (percentages are based on free base). ). Each formulation with 1% w/w of phosphate salt of API had lower viscosity compared to placebo (where the balance is water). While not wishing to be bound by any particular theory, it is believed that the lower viscosity is due to the electrolytic nature of the phosphate. The formulation and placebo viscosities over time are shown in Table 23. The 1% dispersion cream (water-in-oil formulation) exhibited syneresis after 2 and 4 weeks of aging at 40°C, while the 1% lotion and 1% solubilizing cream formulation (oil-in-water formulation ) showed no syneresis. The 1% solubilized cream formulation was generally of higher viscosity than the 1% lotion.

Example 6: Skin Permeation Studies Three different topical formulations of Example 5 (Table 20) and the cream formulation of Example 3 (Table 4) were evaluated for transport across human cadaver skin. The skin permeation data are summarized in Table 24. Significant variation was observed in delivery during the three replicates for each formulation. Variations in transport may be due in part to differences in skin samples (donor, body region, thickness, etc.). In general, the two cream formulations showed higher flux than the lotion or ointment. The cumulative amount of API delivered for the ointment formulation is particularly low compared to the other three formulations, which is at least partially due to the poor spreadability of the ointment resulting in a reduced surface area for delivery. It may be due to what has been brought Consequently, two cream formulations were selected for further development, one as an oil-in-water system (see Example 3 above) and the other as a water-in-oil emulsion system. Based on drug substance solubility, (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate Strengths containing 1.0, 1.5, and 2.0% w/w of salt were developed for oil-in-water creams (solubilized creams), and 1.0, 2.0, and 3 A strength of .0% w/w was developed for water-in-oil creams (dispersion creams). The skin permeation test procedure is described below.

Human Cadaver Skin Transport Study The permeability of APIs in topical formulations was tested using human cadaver skin samples and a Franz diffusion cell. Dermatosegmented human cadaver skin was obtained from a tissue bank, while Franz diffusion cells were custom-made. A human cadaver skin sample sized to fit between the donor and recipient compartments was placed on the Franz diffusion cell. The topical formulation was weighed (20 mg) and placed on glassine paper with the formulation side facing the skin and secured firmly. The dosing chamber was covered with paraffin. The reservoir side was filled with saline containing 4% albumin. The sump was agitated and maintained at 37° C. using a dry block heater (Aungst B., Fatty Acid Skin Penetration Enhancers. Pharm. Res. 1989;6(3):244-247). After 4 hours, a 1 mL sample was removed and replaced with 1 mL of saline + 4% albumin. After 24 hours, the entire sump was collected. It was visually inspected for holes and fissures. The sump side samples were analyzed for API concentration by LC/MS assay.

Mouse Skin Transport Study The permeability of APIs in topical formulations was tested using freshly excised mouse skin samples mounted in Franz diffusion cells. Four days before the experiment, Balb/c mice were shaved using a wax technique. On the morning of the day of the experiment, mice were euthanized and as much depilated skin as possible was excised, washed and kept moist with 37° C. saline until use. A mouse skin sample sized to fit between the donor and recipient compartments was placed between the donor and recipient compartments of the Franz diffusion cell. The opening of the Franz cell was 1 ^cm2 . The topical formulation was weighed (20 mg) and placed on glassine paper, placed formulation side towards the skin and secured firmly. The dosing chamber was covered with paraffin. The reservoir side was filled with saline containing 4% albumin. The sump was agitated and maintained at 37° C. using a dry block heater (Aungst 1989, supra). After 4 hours, a 1 mL sample was removed and replaced with 1 mL of saline + 4% albumin. After 24 hours, the entire sump was collected. It was visually inspected for holes and fissures. The sump side samples were analyzed for API concentration by LC/MS assay.

Effect of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile on transport across human cadaver skin The effect of strength of the solubilized or dispersed cream formulation was also examined and the data are summarized in Table 25. Increase in strength from 1% w/w to 3% w/w for dispersion cream formulation (water-in-oil system) and strength reduction from 1% w/w to 2% w/w for solubilizing cream formulation (water-in-water system) The increase resulted in a significant change in the transport of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile. This means that the flux of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is It suggests that release from each of these formulations is not limiting.

of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile across freshly excised mouse skin Transport was further evaluated using the formulation used in the rodent pharmacology study (Table 26). There was a general trend of increased permeability when the strength of the solubilized cream was increased to 0.5-1.5%, but these trends were not observed with the dispersion formulations. (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-transported across mouse skin over 24 h for solubilized cream The mean cumulative dose of 3-cyclopentylpropanenitrile was about 20 times higher than that seen in the human cadaver skin test (cumulative mean of all experiments).

Based on the solubility of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate, 1 A maximum drug load of .5% was possible with the oil-in-water (solubilized cream) formulation. Among the two cream formulations, the oil-in-water (solubilized cream) product showed better physical stability (see Table 21 above). Strengths greater than 3% in dispersion formulations and greater than 2% in solubilized cream formulations are physically unreliable after several days of storage at controlled room temperature due to drug substance crystallizing out of solution. Note that it was not stable. Based on these results, along with skin permeation studies, manufacturability data, and physical and chemical characterization data obtained during the early stages of formulation, an oil-in-water emulsion system (maximum strength of 1.5% w/w with) was selected for further development.

Example 7: Clinical Treatment of Psoriasis with Formulations Approximately 200 subjects with chronic plaque psoriasis were enrolled in a double-blind, placebo-controlled study. There were 4 dose groups, these were the 3 active dose groups and the vehicle group. Active dose groups were treated with 0.5%, 1.0%, and 1.5% w/w oil-in-water formulations (see Example 3 above). Approximately 50 subjects were randomized to each treatment group. A thin layer of the cream was applied once daily to 20% body surface area of psoriasis vulgaris. Treatment was applied for 84 days and efficacy was measured by changes in lesion scores (Figure 2). The lesion score is a metric that assesses the amount of erythema, desquamation and thickness of the plaque. Twenty-five percent of patients randomized to 1% w/w or 1.5% w/w of API had lesions that had cleared or nearly cleared at 12 weeks, compared with 25% in the vehicle group. was 6%.

Photographs were obtained from subjects who signed informed consent for photographs at a subset of lesion sites. Images were obtained at baseline (before the first application of study treatment) and on Day 84 (the day of the last application of study treatment) (see Figures 3-7). These photographs are representative of a subset of subjects treated with an oil-in-water formulation.

Example 8 Murine Skin Contact Delayed Hypersensitivity Test The formulations described herein can also be tested for their efficacy in the T cell-induced murine delayed hypersensitivity test model. The murine cutaneous delayed-type hypersensitivity (DTH) response has been proposed as a valid animal model for clinical contact dermatitis and other T-lymphocyte-mediated immune diseases of the skin such as psoriasis (Immunol Today. 1998). Jan; 19(1):37-44). Murine DTH shares multiple features with psoriasis, including immune infiltrates, concomitant increases in inflammatory cytokines, and corneocyte hyperproliferation. Furthermore, many classes of drugs that have efficacy in treating psoriasis in the medical setting are also effective inhibitors of DTH responses in mice (Agents Action. 1993 Jan;38(1-2)116- 21).

On days 0 and 1, Balb/c mice are sensitized by topical application of the antigen 2,4, dinitro-fluorobenzene (DNFB) to their shaved abdomens. On day 5, the mouse ear thickness is measured using an engineer's micrometer. This measurement is recorded and used as a baseline. The animals are then challenged by topical application of DNFB at a concentration of 0.2% in a total of 20 μL (10 μL on the inner and 10 μL on the external) to both ears. Twenty-four to seventy-two hours after challenge, ear thickness is measured again. Treatment with test formulations is given throughout the sensitization and challenge phases (Days 1-7) or prior to the challenge and throughout the challenge phase (usually the afternoon of Day 4-7). day). Treatment with test compounds (at different concentrations) is administered topically (topical application of therapeutic agent to the ear). Efficacy of the test formulation is indicated by a reduction in ear edema compared to the untreated condition. Compounds that cause a 20% or greater reduction are considered effective. In some experiments, mice are challenged but not sensitized (negative controls).

The inhibitory effect (inhibitory activity of the JAK-STAT pathway) of test formulations can be confirmed by immunohistochemical analysis. Activation of the JAK-STAT pathway(s) leads to the formation and translocation of functional transcription factors. Furthermore, the influx of immune cells and increased corneocyte proliferation should also lead to changes in characteristic expression profiles in the ear that can be assessed and quantified. Formalin-fixed, paraffin-embedded ear sections (taken after the challenge phase in the DTH model) were immunohistologically analyzed using an antibody that specifically interacts with phosphorylated STAT3 (clone 58E12, Cell Signaling Technologies). Submit for analysis. For comparison, in the DTH model, mouse ears are treated with test formulation, vehicle, dexamethasone (a clinically effective treatment for psoriasis), or no treatment. Test formulations and dexamethasone can produce similar transcriptional changes, both qualitatively and quantitatively, and both test formulations and dexamethasone can reduce the number of invading cells. Local administration of a test compound can cause an inhibitory effect, ie a reduction in the number of invading cells and an inhibition of transcriptional changes.

The present invention includes the following.
[Invention 1]
A pharmaceutical formulation for topical skin application,
an oil-in-water emulsion, and (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutical A pharmaceutical formulation containing a therapeutically effective amount of a therapeutic agent that is an acceptable salt.
[Invention 2]
The pharmaceutical formulation according to invention 1 above, wherein the emulsion comprises water, an oil component and an emulsifier component.
[Invention 3]
The pharmaceutical formulation of invention 2 above, wherein the oil component is present in an amount of about 10% to about 40% by weight of the formulation.
[Invention 4]
The pharmaceutical formulation of invention 2 above, wherein the oil component is present in an amount of about 17% to about 27% by weight of the formulation.
[Invention 5]
The pharmaceutical formulation of invention 2 above, wherein the oil component is present in an amount of about 20% to about 27% by weight of the formulation.
[Invention 6]
A pharmaceutical formulation according to any one of inventions 2 to 5 above, wherein the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides and silicone oils.
[Invention 7]
6. The oil component according to any one of Inventions 2 to 5 above, wherein the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides and dimethicone. Pharmaceutical formulation.
[Invention 8]
The pharmaceutical formulation according to invention 2 above, wherein the oil component comprises a sealant component.
[Invention 9]
9. The pharmaceutical formulation of invention 8 above, wherein the sealant component is present in an amount from about 2% to about 15% by weight of the formulation.
[Invention 10]
9. The pharmaceutical formulation of invention 8 above, wherein the sealant component is present in an amount of about 5% to about 10% by weight of the formulation.
[Invention 11]
A pharmaceutical formulation according to any one of inventions 8 to 10 above, wherein the sealant component comprises petrolatum.
[Invention 12]
11. The pharmaceutical formulation according to any one of inventions 8-10 above, wherein the sealant component comprises white petrolatum.
[Invention 13]
The pharmaceutical formulation according to invention 2 above, wherein the oil component comprises a curing agent component.
[Invention 14]
14. The pharmaceutical formulation of invention 13 above, wherein the sclerosing agent component is present in an amount of about 2% to about 8% by weight of the formulation.
[Invention 15]
14. The pharmaceutical formulation of invention 13 above, wherein the sclerosing agent component is present in an amount of about 3% to about 6% by weight of the formulation.
[Invention 16]
14. The pharmaceutical formulation of invention 13 above, wherein the sclerosing agent component is present in an amount of about 4% to about 7% by weight of the formulation.
[Invention 17]
17. A pharmaceutical formulation according to any one of inventions 13 to 16 above, wherein the sclerosing agent component comprises one or more substances independently selected from fatty alcohols.
[Invention 18]
17. A pharmaceutical formulation according to any one of inventions 13-16 above, wherein the hardener component comprises one or more substances independently selected from C12-20 fatty alcohols.
[Invention 19]
17. A pharmaceutical formulation according to any one of inventions 13-16 above, wherein the hardener component comprises one or more substances independently selected from C16-18 fatty alcohols.
[Invention 20]
17. A pharmaceutical formulation according to any one of inventions 13 to 16 above, wherein the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
[Invention 21]
The pharmaceutical formulation according to invention 2 above, wherein the oil component comprises an emollient component.
[Invention 22]
22. The pharmaceutical formulation of invention 21 above, wherein the emollient component is present in an amount of about 5% to about 15% by weight of the formulation.
[Invention 23]
22. The pharmaceutical formulation of invention 21 above, wherein the emollient component is present in an amount of about 7% to about 13% by weight of the formulation.
[Invention 24]
24. A pharmaceutical formulation according to any one of inventions 21 to 23 above, wherein the emollient component comprises one or more substances independently selected from mineral oils and triglycerides.
[Invention 25]
24. A pharmaceutical formulation according to any one of inventions 21 to 23 above, wherein the emollient component comprises one or more substances independently selected from light mineral oils and medium chain triglycerides.
[Invention 26]
24. A pharmaceutical formulation according to any one of inventions 21 to 23 above, wherein the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides and dimethicone.
[Invention 27]
27. The pharmaceutical formulation according to any one of inventions 2-26 above, wherein water is present in an amount of about 35% to about 65% by weight of the formulation.
[Invention 28]
27. The pharmaceutical formulation according to any one of inventions 2-26 above, wherein water is present in an amount of about 40% to about 60% by weight of the formulation.
[Invention 29]
27. The pharmaceutical formulation according to any one of inventions 2-26 above, wherein water is present in an amount of about 45% to about 55% by weight of the formulation.
[Invention 30]
30. The pharmaceutical formulation according to any one of inventions 2-29 above, wherein the emulsifier component is present in an amount of from about 1% to about 9% by weight of the formulation.
[Invention 31]
30. The pharmaceutical formulation according to any one of inventions 2-29 above, wherein the emulsifier component is present in an amount of about 2% to about 6% by weight of the formulation.
[Invention 32]
30. The pharmaceutical formulation according to any one of inventions 2-29 above, wherein the emulsifier component is present in an amount of about 3% to about 5% by weight of the formulation.
[Invention 33]
30. The pharmaceutical formulation according to any one of inventions 2-29 above, wherein the emulsifier component is present in an amount of about 4% to about 7% by weight of the formulation.
[Invention 34]
The medicament according to any one of Inventions 2 to 29 above, wherein the pharmaceutical formulation comprises an emulsifier component and a hardener component, and the total amount of the emulsifier component and the hardener component is at least about 8% by weight of the formulation. pharmaceutical formulation.
[Invention 35]
35. A pharmaceutical formulation according to any one of inventions 2 to 34 above, wherein the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters.
[Invention 36]
35. A pharmaceutical formulation according to any one of inventions 2-34 above, wherein the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.
[Invention 37]
A pharmaceutical formulation according to any one of inventions 1 to 36 above, wherein the pharmaceutical formulation further comprises a stabilizer component.
[Invention 38]
38. The pharmaceutical formulation of invention 37 above, wherein the stabilizer component is present in an amount of about 0.05% to about 5% by weight of the formulation.
[Invention 39]
38. The pharmaceutical formulation of invention 37 above, wherein the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the formulation.
[Invention 40]
38. The pharmaceutical formulation of invention 37 above, wherein the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the formulation.
[Invention 41]
41. A pharmaceutical formulation according to any one of inventions 37-40 above, wherein the stabilizer component comprises one or more substances independently selected from polysaccharides.
[Invention 42]
The pharmaceutical formulation according to any one of inventions 37-40 above, wherein the stabilizer component comprises xanthan gum.
[Invention 43]
The pharmaceutical formulation according to any one of Inventions 1 to 42 above, which further comprises a solvent component.
[Invention 44]
44. The pharmaceutical formulation of invention 43 above, wherein the solvent component is present in an amount of about 10% to about 35% by weight of the formulation.
[Invention 45]
44. The pharmaceutical formulation of invention 43 above, wherein the solvent component is present in an amount of about 15% to about 30% by weight of the formulation.
[Invention 46]
44. The pharmaceutical formulation of invention 43 above, wherein the solvent component is present in an amount of about 20% to about 25% by weight of the formulation.
[Invention 47]
47. The pharmaceutical formulation according to any one of inventions 43 to 46 above, wherein the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.
[Invention 48]
47. A pharmaceutical formulation according to any one of inventions 43 to 46 above, wherein the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
[Invention 49]
49. The pharmaceutical formulation of any one of Inventions 1-48 above, wherein the therapeutic agent is present in an amount of from about 0.5% to about 1.5% by weight of the formulation, based on free base.
[Invention 50]
49. The pharmaceutical formulation of any one of inventions 1-48 above, wherein the therapeutic agent is present in an amount of about 0.5% by weight of the formulation, based on free base.
[Invention 51]
49. The pharmaceutical formulation of any one of inventions 1-48 above, wherein the therapeutic agent is present in an amount of about 1% by weight of the formulation, based on free base.
[Invention 52]
49. The pharmaceutical formulation of any one of Inventions 1-48 above, wherein the therapeutic agent is present in an amount of about 1.5% by weight of the formulation, based on free base.
[Invention 53]
The therapeutic agent is (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate , the pharmaceutical formulation according to any one of Inventions 1 to 52 above.
[Invention 54]
water from about 35% to about 65% by weight of the formulation;
an oil component from about 10% to about 40% by weight of the formulation;
an emulsifier component from about 1% to about 9% by weight of the formulation;
a solvent component from about 10% to about 35% by weight of the formulation;
from about 0.05% to about 5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl, based on the free base. -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof; Pharmaceutical formulations as described.
[Invention 55]
water from about 40% to about 60% by weight of the formulation;
an oil component, from about 15% to about 30% by weight of the formulation;
an emulsifier component from about 2% to about 6% by weight of the formulation;
a solvent component from about 15% to about 30% by weight of the formulation;
from about 0.1% to about 2% by weight of the formulation of a stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl, based on the free base. -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof; Pharmaceutical formulations as described.
[Invention 56]
water from about 45% to about 55% by weight of the formulation;
an oil component, from about 17% to about 27% by weight of the formulation;
an emulsifier component from about 3% to about 5% by weight of the formulation;
a solvent component from about 20% to about 25% by weight of the formulation;
from about 0.3% to about 0.5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3, based on the free base. -cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. 1. Pharmaceutical formulation according to 1.
[Invention 57]
water from about 45% to about 55% by weight of the formulation;
an oil component, from about 17% to about 27% by weight of the formulation;
an emulsifier component from about 4% to about 7% by weight of the formulation;
a solvent component from about 20% to about 25% by weight of the formulation;
from about 0.3% to about 0.5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3, based on the free base. -cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. 1. Pharmaceutical formulation according to 1.
[Invention 58]
the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides and dimethicone;
the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;
the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols;
the stabilizer component comprises one or more substances independently selected from polysaccharides;
The pharmaceutical formulation according to any one of Inventions 54-57 above.
[Invention 59]
the oil component comprises one or more materials independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides and dimethicone;
the emulsifier component comprises one or more materials independently selected from glyceryl stearate and polysorbate 20;
the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol;
the stabilizer component comprises xanthan gum;
The pharmaceutical formulation according to any one of Inventions 54-57 above.
[Invention 60]
water from about 35% to about 60% by weight of the formulation;
a sealant component from about 2% to about 15% by weight of the formulation;
a curing agent component from about 2% to about 8% by weight of the formulation;
an emollient component from about 5% to about 15% by weight of the formulation;
an emulsifier component from about 1% to about 9% by weight of the formulation;
from about 0.05% to about 5% by weight of the formulation of a stabilizer component;
from about 10% to about 35% by weight of the formulation of the solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ Pharmaceutical formulation according to Invention 1 above, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof .
[Invention 61]
water from about 40% to about 60% by weight of the formulation;
a sealant component from about 5% to about 10% by weight of the formulation;
a curing agent component from about 2% to about 8% by weight of the formulation;
an emollient component, from about 7% to about 12% by weight of the formulation;
an emulsifier component from about 2% to about 6% by weight of the formulation;
from about 0.1% to about 2% by weight of the formulation of a stabilizer component;
from about 15% to about 30% by weight of the formulation of the solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ Pharmaceutical formulation according to Invention 1 above, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof .
[Invention 62]
water from about 45% to about 55% by weight of the formulation;
a sealant component from about 5% to about 10% by weight of the formulation;
a curing agent component from about 3% to about 6% by weight of the formulation;
an emollient component, from about 7% to about 13% by weight of the formulation;
an emulsifier component from about 3% to about 5% by weight of the formulation;
from about 0.3% to about 0.5% by weight of the formulation of a stabilizer component;
from about 20% to about 25% by weight of the formulation of a solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ Pharmaceutical formulation according to Invention 1 above, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof .
[Invention 63]
water from about 45% to about 55% by weight of the formulation;
a sealant component from about 5% to about 10% by weight of the formulation;
a curing agent component from about 4% to about 7% by weight of the formulation;
an emollient component, from about 7% to about 13% by weight of the formulation;
an emulsifier component from about 4% to about 7% by weight of the formulation;
from about 0.3% to about 0.5% by weight of the formulation of a stabilizer component;
from about 20% to about 25% by weight of the formulation of a solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[ Pharmaceutical formulation according to Invention 1 above, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof .
[Invention 64]
water from about 45% to about 55% by weight of the formulation;
a sealant component of about 7% by weight of the formulation;
a curing agent component from about 4.5% to about 5% by weight of the formulation;
an emollient component at about 10% by weight of the formulation;
an emulsifier component from about 4% to about 4.5% by weight of the formulation;
a stabilizer component at about 0.4% by weight of the formulation;
about 22% by weight of the formulation of the solvent component, and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[4-(7H- A pharmaceutical formulation according to Invention 1 above, comprising pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.
[Invention 65]
65. The pharmaceutical formulation according to any one of inventions 60-64 above, wherein the total amount of hardener component and emulsifier component is at least about 8% by weight of the formulation.
[Invention 66]
the sealant component comprises petroleum jelly;
the curing agent component comprises one or more substances independently selected from one or more fatty alcohols;
the emollient component comprises one or more substances independently selected from mineral oils and triglycerides;
the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;
the stabilizer component comprises one or more substances independently selected from polysaccharides;
the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols;
The pharmaceutical formulation according to any one of Inventions 60-65 above.
[Invention 67]
The sealant component comprises white petrolatum,
the curing agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol;
the emollient component comprises one or more materials independently selected from light mineral oil, medium chain triglycerides and dimethicone;
the emulsifier component comprises one or more materials independently selected from glyceryl stearate and polysorbate 20;
the stabilizer component comprises xanthan gum;
the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol;
The pharmaceutical formulation according to any one of Inventions 60-65 above.
[Invention 68]
68. A pharmaceutical formulation according to any one of inventions 1-67 above, further comprising an antimicrobial preservative component.
[Invention 69]
69. The pharmaceutical formulation of invention 68 above, wherein the antimicrobial preservative component is present from about 0.05% to about 3% by weight of the formulation.
[Invention 70]
69. The pharmaceutical formulation of invention 68 above, wherein the antimicrobial preservative component is present from about 0.1% to about 1% by weight of the formulation.
[Invention 71]
71. A pharmaceutical formulation according to any one of inventions 68-70 above, wherein the antimicrobial preservative component comprises one or more substances independently selected from alkylparabens and phenoxyethanol.
[Invention 72]
71. A pharmaceutical formulation according to any one of inventions 68-70 above, wherein the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben and phenoxyethanol.
[Invention 73]
The pharmaceutical formulation according to any one of inventions 1-72 above, further comprising a chelating agent component.
[Invention 74]
74. The pharmaceutical formulation of invention 73 above, wherein the chelating agent component comprises disodium edetate.
[Invention 75]
A method of treating a skin disorder in a patient in need of such treatment, comprising administering the pharmaceutical formulation according to any one of Inventions 1 to 74 above to an area of the patient's skin.
[Invention 76]
76. The method of invention 75 above, wherein the skin disorder is atopic dermatitis or psoriasis.
[Invention 77]
76. The method of invention 75 above, wherein the skin disorder is psoriasis.
[Invention 78]
76. The method according to invention 75 above, wherein the skin disorder is skin sensitization, skin irritation, rash, contact dermatitis or allergic contact sensitization.
[Invention 79]
76. The method of invention 75 above, wherein the skin disorder is bullous skin disorder.
[Invention 80]
80. The method of invention 79 above, wherein the bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).
[Invention 81]
A pharmaceutical formulation according to any one of the above inventions 1 to 74 for treating skin disorders in a patient in need of such treatment.
[Invention 82]
Use of the pharmaceutical preparation according to any one of Inventions 1 to 74 above for preparing a drug for treating skin disorders in a patient in need of treatment.
Various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the claims. Each reference cited in this application is hereby incorporated by reference in its entirety.

Claims (22)

1. A pharmaceutical composition for treating a skin disorder in a human patient in need thereof, comprising an oil-in-water emulsion, said composition being applied to the skin of said patient,
The oil-in-water emulsion is
water,
oil component,
emulsifier component,
a solvent component, and
1:1 (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d] from about 0.5% to about 1.5% by weight of the emulsion, based on the free base pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate
includes;
the oil-in-water emulsion in the composition is a solubilized cream, and the pH of the oil-in-water emulsion is 3.6 or less;
said treatment is one or more of inhibiting skin disorders and reducing skin disorders;
wherein the skin disorder is an autoimmune skin disorder;
Composition. 2. The composition of claim 1, applied continuously for up to 84 days. 3. The composition of claim 1 or 2, wherein the autoimmune skin disorder is psoriasis or atopic dermatitis. wherein said water is present in an amount ranging from about 40% to about 60% by weight of said composition and said oil component is present in an amount ranging from about 17% to about 27% by weight of said composition; Item 4. The composition according to any one of Items 1 to 3. The composition of any one of claims 1-4, further comprising a stabilizer component. 1:1 (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- at about 1.5% by weight of the emulsion, based on the free base A composition according to any preceding claim, wherein 1H-pyrazol-1-yl]propanenitrile phosphate is present. A composition according to any preceding claim, wherein the pH of the oil-in-water emulsion is between 2.9 and 3.6. 1. A pharmaceutical composition for inhibiting JAK1 and/or JAK2 in a human patient suffering from a skin disorder comprising an oil-in-water emulsion, said composition being applied to the skin of said patient,
The oil-in-water emulsion is
water,
oil component,
emulsifier component,
a solvent component, and
1:1 (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d] from about 0.5% to about 1.5% by weight of the emulsion, based on the free base pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate
includes;
The oil-in-water emulsion in the composition is a solubilized cream, and the pH of the oil-in-water emulsion is 3.6 or less.
Composition. 9. The composition of claim 8, applied continuously for up to 84 days. 10. The composition of claim 8 or 9, wherein said skin disorder is an autoimmune skin disorder. 11. The composition of claim 10, wherein said autoimmune skin disorder is atopic dermatitis. wherein said water is present in an amount ranging from about 40% to about 60% by weight of said composition and said oil component is present in an amount ranging from about 17% to about 27% by weight of said composition; Item 12. The composition according to any one of items 8 to 11. A composition according to any one of claims 8 to 12, further comprising a stabilizer component. 1:1 (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- at about 1.5% by weight of the emulsion, based on the free base A composition according to any one of claims 8 to 13, wherein 1H-pyrazol-1-yl]propanenitrile phosphate is present. A composition according to any one of claims 8 to 14, wherein the pH of the oil-in-water emulsion is between 2.9 and 3.6. A pharmaceutical composition for treating atopic dermatitis in a human patient comprising an oil-in-water emulsion, said composition being applied to the skin of said patient,
The oil-in-water emulsion is
water,
oil component,
emulsifier component,
a solvent component, and
1:1 (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d] from about 0.5% to about 1.5% by weight of the emulsion, based on the free base pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate
includes;
the oil-in-water emulsion in the composition is a solubilized cream, and the pH of the oil-in-water emulsion is 3.6 or less;
said treatment is one or more of inhibiting atopic dermatitis and reducing atopic dermatitis;
Composition. 17. The composition of claim 16, applied continuously for up to 84 days. wherein said water is present in an amount ranging from about 40% to about 60% by weight of said composition and said oil component is present in an amount ranging from about 17% to about 27% by weight of said composition; 18. The composition of item 16 or 17. The composition of any one of claims 16-18, further comprising a stabilizer component. A composition according to any one of claims 16 to 19, wherein the pH of said oil-in-water emulsion is between 2.9 and 3.6. A composition according to any one of claims 16 to 20, wherein the treatment is alleviation of atopic dermatitis. 1:1 (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- at about 1.5% by weight of the emulsion, based on the free base A composition according to any one of claims 16 to 21, wherein 1H-pyrazol-1-yl]propanenitrile phosphate is present.

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